Anemia is a decrease in the number of red blood cells (RBCs) as measured by the red cell count, the hematocrit, or the red cell hemoglobin content.
In adult males, anemia is defined as any of the following:
In adult females, anemia is defined as any of the following:
For infants and children, normal values vary with age, necessitating use of age-related tables (see table Age-Specific Values for Hemoglobin and Hematocrit ).
Anemia is not a diagnosis; it is a manifestation of an underlying disorder (see Etiology of Anemia ). Thus, even mild, asymptomatic anemia should be investigated so that the primary problem can be diagnosed and treated.
Anemia is usually suspected based on the history and physical examination. Common symptoms and signs of anemia include
History and physical examination are followed by laboratory testing with a complete blood count, reticulocyte count, and peripheral smear. The differential diagnosis (and cause of anemia) can then be further refined based on the results of testing.
The history should address
Anemia has many risk factors. For example, a vegan diet predisposes to vitamin B12 deficiency anemia , whereas alcohol use disorder increases the risk of folate deficiency anemia . A number of hemoglobinopathies are inherited, and certain medications and infections predispose to hemolysis . Cancer, rheumatic disorders, and chronic inflammatory disorders can suppress red cell production. Autoimmune disorders such as systemic lupus erythematosus or lymphoma can predispose to autoimmune hemolytic anemia .
The symptoms of anemia are neither sensitive nor specific and do not help differentiate between types of anemias. Symptoms reflect compensatory responses to tissue hypoxia and usually develop when the hemoglobin level falls well below the patient's individual baseline. Symptoms are generally more pronounced in patients with limited cardiopulmonary reserve or when the anemia develops very rapidly.
Symptoms such as weakness, fatigue, drowsiness, angina, syncope, and dyspnea on exertion can indicate anemia. Vertigo, headache, pulsatile tinnitus, amenorrhea, loss of libido, and gastrointestinal (GI) symptoms may also occur.
Heart failure or shock can develop in patients with severe tissue hypoxia or hypovolemia.
Certain symptoms may suggest the cause of the anemia. For example, melena, epistaxis, hematochezia, hematemesis, or menorrhagia indicates bleeding. Jaundice and dark urine, in the absence of liver disease, suggest hemolysis. Weight loss may suggest cancer. Diffuse severe bone or chest pain may suggest sickle cell disease , and stocking-glove paresthesias may suggest vitamin B12 deficiency .
A complete physical examination is necessary. Signs of anemia itself are neither sensitive nor specific; however, pallor is common with severe anemia (ie, hemoglobin < 7 g/dL [ < 70 g/L]).
Signs of many underlying disorders are more diagnostically accurate than are signs of anemia. Heme-positive stool identifies gastrointestinal bleeding . Hemorrhagic shock (eg, hypotension, tachycardia, pallor, tachypnea, diaphoresis, confusion) may result from acute bleeding. Jaundice may suggest hemolysis. Splenomegaly may occur with hemolysis,hemoglobinopathies, systemic rheumatic diseases, myeloproliferative disorders, infections, or cancers. Peripheral neuropathy suggests vitamin B12 deficiency . Fever and heart murmurs suggest infective endocarditis . Rarely, high-output heart failure develops as a compensatory response to anemia-induced tissue hypoxia.
Laboratory evaluation begins with a complete blood count (CBC), including white blood cell (WBC) and platelet counts, RBC indices and morphology, and examination of the peripheral smear. RBC indices include mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cell distribution width (RDW). The reticulocyte count demonstrates how well the bone marrow is compensating for the anemia.
Subsequent tests are selected on the basis of these results and on the clinical presentation. These tests aid in further characterizing the anemia and determining its cause and may include blood chemistries, ferritin, haptoglobin, direct antiglobulin test, folate, and vitamin B12 measurement, as well as urinalysis, fecal occult blood determination, and sometimes bone marrow aspiration and biopsy. Recognition of general diagnostic patterns can expedite the diagnosis (see table Characteristics of Common Anemias ).
Characteristics of Common AnemiasCharacteristics of Common Anemias
Etiology or Type
Blood loss, acute
Normochromic-normocytic, with polychromatophilia
If severe, possible nucleated RBCs and left shift of the WBCs
Blood loss, chronic
Same as iron deficiency
Same as iron deficiency
Same as vitamin B12 deficiency
Nutritional deficiency and malabsorption (in sprue, pregnancy, infancy, or alcohol use disorder)
Normoblastic erythroid hyperplasia
Increased RBC osmotic fragility
Shortened survival of labeled RBCs
Normoblastic erythroid hyperplasia
Increased RBC osmotic fragility
Shortened survival of labeled RBCs
Positive direct antiglobulin test
Marrow erythroid hyperplasia
Increased serum indirect bilirubin and LDH, low haptoglobin
Increased stool and urine urobilinogen
Hemoglobinuria in intravascular hemolysis
Infection, cancer, chronic inflammation, or renal disease
Normochromic-normocytic early, then microcytic
Normal or increased iron stores
Decreased serum iron
Decreased total iron-binding capacity
Normal or increased marrow iron content
Microcytic, with anisocytosis and poikilocytosis
Hyperplastic marrow, with delayed hemoglobination
Possible achlorhydria, smooth tongue, angular cheilosis, and spoon nails
Absent stainable marrow iron
Increased total iron-binding capacity
Low serum ferritin
Normochromic-normocytic (may be macrocytic)
Failed marrow aspiration (often) or evident hypoplasia of erythroid series or of all elements
Anisocytosis and poikilocytosis (eg, teardrop cells)
Early granulocyte precursors
Marrow aspiration possibly failing or showing leukemia, myeloma, myelofibrosis, or metastatic cells
Marrow infiltration with infectious granulomas, tumors, fibrosis, or lipid histiocytosis
Possible hepatomegaly and splenomegaly
Possible bone changes (osteosclerosis)
Red cell agglutination
Follows exposure to cold
Results from a cold agglutinin or hemolysin test
Hemoglobinuria, sometimes with frankly dark morning urine
Smooth muscle dystonia causing abdominal pain, esophageal spasm, erectile dysfunction
Variable degree of bone marrow failure (cytopenias)
Anisocytosis and poikilocytosis
Some sickle cells in peripheral smear
Sickling of all RBCs in preparation with hypoxia or hyperosmolar exposure
Most common in people of African ancestry in the United States
Hb S detected during electrophoresis
Bone changes on x-ray
Stroke and other thrombotic events
Possibly painful vaso-occlusive crises and leg ulcers, stroke
Usually hypochromic but dimorphic with normocytes and macrocytes
Hyperplastic marrow, with delayed hemoglobination
Usually stainable marrow iron (plentiful), but can be reduced
Some congenital forms respond to vitamin B6 administration
Can be part of a myelodysplastic syndrome
Anisocytosis and poikilocytosis in homozygotes
Nucleated RBCs in homozygotes
Elevated Hb A2 and Hb F (in beta-thalassemia)
Mediterranean ancestry (common)
In homozygotes, anemia from infancy
Bone changes on radiographs
Elevated methylmalonic acid and homocysteine
Antibodies to intrinsic factor in serum (pernicious anemia)
Frequently, GI and CNS symptoms
CNS = central nervous system; GI = gastrointestinal; Hb = hemoglobin; LDH = lactic dehydrogenase; MCHC = mean corpuscular hemoglobin concentration; RBC = red blood cell; WBC = white blood cell.
The automated CBC directly measures hemoglobin, RBC count, WBC count, and platelet count, plus mean corpuscular volume (MCV), which is a measure of RBC volume. Hematocrit, which is a measure of the percentage of blood made up of RBCs, mean corpuscular hemoglobin (MCH), which is a measure of the hemoglobin content in individual RBCs but is of no clinical significance, and mean corpuscular hemoglobin concentration (MCHC), which is a measure of the hemoglobin concentration in individual RBCs are calculated values.
The diagnostic criterion for anemia is
For infants and children, normal values vary with age, necessitating use of age-related tables (see table Age-Specific Values for Hemoglobin and Hematocrit ).
RBC populations are termed microcytic (small cells) if MCV is < 80 fL, and macrocytic (large cells) if MCV is >100 fL. However, because reticulocytes are also larger than mature red cells, large numbers of reticulocytes can elevate the MCV.
Automated techniques can also determine the degree of variation in RBC size, expressed as the RBC volume distribution width (RDW). A high RDW may be the only indication of simultaneous microcytic and macrocytic disorders; such a pattern may result in a normal MCV, which measures only the mean value. The term hypochromia refers to RBC populations in which the MCHC is < 30%. RBC populations with a normal MCHC value are normochromic. Spherocytes can have an elevated MCHC. Red cells defend their MCHC over their MCV (preserving hemoglobin at the expense of RBC size), which is why microcytosis occurs with iron deficiency, impaired hemoglobin synthesis, or the erythrocytosis in polycythemia vera .
The RBC indices can help indicate the mechanism of anemia and narrow the number of possible causes.
Microcytic indices occur with altered heme or globin synthesis. The most common causes are iron deficiency , thalassemia , and related hemoglobin-synthesis defects. In some patients with the anemia of chronic disease , the MCV is microcytic or borderline microcytic.
Macrocytic indices occur with impaired DNA synthesis (eg, due to vitamin B12 deficiency , folate deficiency alcohol use disorder because of abnormalities of the cell membrane. Acute bleeding may briefly produce macrocytic indices because of the early release of large young reticulocytes.
Normocytic indices occur in anemias resulting from deficient erythropoietin (EPO) production or inadequate response to it (hypoproliferative anemias). Hemorrhage, before iron deficiency develops, usually results in normocytic and normochromic anemia unless the number of reticulocytes is excessive.
The peripheral smear can suggest the presence or cause of a hemolytic anemia, demonstrate alterations in RBC structure, confirm the presence of thrombocytopenia (versus artifactual platelet clumping) and be used to identify immature granulocyte and abnormal lymphocyte morphology, often flagged by automated blood cell analyzers. It can detect other abnormalities (eg, malaria and other parasites, intracellular RBC or granulocyte inclusions) that can occur despite normal automated blood cell counts. RBC injury may be identified by finding RBC fragments (schistocytes), oxidative damage (bite or blister cells) or evidence of significant membrane alterations from sickled cells, oval-shaped cells (ovalocytes) or spherocytic cells. Target cells (thin RBCs with a central dot of hemoglobin) are RBCs with insufficient hemoglobin or excess cell membrane (eg, due to hemoglobinopathies or liver disorders). The peripheral smear can also reveal variation in RBC shape (poikilocytosis) and size (anisocytosis).